Quercetin Alleviates the Progression of Chronic Rhinosinusitis Without Nasal Polyps by Inhibiting Nasal Mucosal Inflammation and Epithelial Apoptosis

Chronic rhinosinusitis (CRS) is a common chronic inflammatory upper respiratory tract, has a major subtype of CRS without nasal polyps (CRSsNP), constituting a great global health problem. Quercetin exerts the important roles in several inflammatory diseases. However, its function in CRSsNP remains unclear. In this study, quercetin dose-dependently alleviated allergic nasal symptoms of increased frequencies of sneezing and nasal scratching in Staphylococcus aureus-constructed CRSsNP mice. Importantly, quercetin attenuated the histopathological changes of nasal mucosa tissue in model mice, including mucosal thickening, glandular hyperplasia, noticeable mast cells, and inflammatory cell infiltration. Concomitantly, quercetin alleviated the increased mucosal inflammation in CRSsNP mice by suppressing the transcripts and releases of pro-inflammatory IL-1 beta, IL-6, and IL-4. Notably, quercetin restrained X-box binding protein 1 (XBP1)-mediated activation of the HIF-1 alpha/wnt-beta-catenin axis in nasal mucosal tissues in CRSsNP model. Intriguingly, intranasal instillation of Lv-XBP1 offset the protective efficacy of quercetin against the progression of CRSsNP by suppressing the production of inflammatory cytokine IL-1 beta, IL-6, and IL-4, frequency of sneezing and nasal scratching, and histopathological changes of nasal mucosa tissues. In vitro, higher expression of XBP1 was observed in human nasal epithelial cells (HNECs) of CRSsNP relative to the normal HNECs. Moreover, elevation of XBP1 by Lv-XBP1 treatment suppressed cell proliferation and increased apoptosis of CRSsNP HNECs. Mechanistically, XBP1 overexpression increased the expression of HIF-1 alpha and beta-catenin, indicating the activation of the HIF-1 alpha/wnt-beta-catenin axis. Nevertheless, treatment with quercetin inhibited XBP1-induced cell apoptosis and reversed XBP1-mediated inhibition in cell proliferation in HNECs, as well as the activation of the HIF-1 alpha/wnt-beta-catenin axis. Thus, these findings reveal that quercetin may attenuate the progression of CRSsNP by inhibiting nasal mucosal inflammation and epithelial barrier dysfunction via blocking the XBP1/HIF-1 alpha/wnt-beta-catenin pathway, supporting a promising agent against CRSsNP.